Résumé : IMPORTANCE Suicidal behavior is a leading cause of injury and death worldwide, and previous cross-sectional studies have demonstrated that nonmedical use of prescription drugs (NMUPD) was associated with suicidality. However, there is not any study in China having examined the longitudinal relationships between NMUPD, suicidal ideation, and suicidal attempts, as well as explored the potential mediating effects of depressive symptoms. OBJECTIVE To determine whether baseline NMUPD was associated with subsequent suicidal ideation and attempts while controlling for depressive symptoms and to determine whether the increased risks were mediated by depressive symptoms. DESIGN, SETTING, AND PARTICIPANTS In this longitudinal study, a total of 3273 students in randomly selected schools in Guangzhou were surveyed from 2009 to 2010 (response rate, 96.8%) and followed up at 1 year (2011-2012; retention rate, 96.1%). The dates of data analysis were October 9, 2015, to October 15, 2015; additional data analysis occurred March 23, 2016, to March 29, 2016. MAIN OUTCOMES AND MEASURES Suicidal ideation, suicidal attempts, NMUPD, depressive symptoms, and alcohol-related problems. RESULTS Overall, 3273 adolescents (mean [SD] age, 13.7 [1.0] years) were recruited for this study. The final results showed that after controlling for sociodemographic information (including sex, age, household socioeconomic status, and living arrangements), baseline depressive symptoms, baseline alcohol-related problems, baseline suicidal ideation, and baseline suicidal attempts, baseline opioids misuse (adjusted odds ratio [AOR], 2.31; 95%CI, 1.30-4.11), sedatives misuse (AOR, 4.46; 95%CI, 1.54-7.94), and nonmedical use of any prescription drug (AOR, 1.97; 95%CI, 1.21-3.23) were positively associated with suicidal ideation at follow-up. Additionally, baseline opioid misuse (AOR, 3.39; 95%CI, 1.33-5.63) and nonmedical use of any prescription drug (AOR, 2.91; 95%CI, 1.26-3.71) were also associated with subsequent suicidal attempts after controlling for sex, age, household socioeconomic status, living arrangements, depressive symptoms, alcohol-related problems, suicidal ideation, and suicidal attempts at baseline. There were significant standardized indirect effects of baseline opioids misuse on subsequent suicidal ideation (standardized β estimate = 0.020; 95%CI, 0.010-0.030) and suicidal attempts (standardized β estimate = 0.009; 95%CI, 0.004-0.015) through depressive symptoms; the standardized indirect effect of baseline sedatives misuse on subsequent suicidal ideation through depressive symptoms was also significant (standardized β estimate = 0.016; 95%CI, 0.005-0.026). CONCLUSIONS AND RELEVANCE In this study, NMUPD at baseline was associated with subsequent suicidal ideation and attempts. These findings support that proper surveillance systems with the potential to reduce adolescent suicidality should be established to control and supervise suicidality and NMUPD among Chinese adolescents.